心包脂肪过多症对心血管的影响及遗传学

Rämö Joel T, Kany Shinwan, Hou Cody R, Friedman Samuel F, Roselli Carolina, Nauffal Victor, Koyama Satoshi, Karjalainen Juha, Maddah Mahnaz, Palotie Aarno, Ellinor Patrick T, Pirruccello James P

Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.

medRxiv. 2023 Jul 18:2023.07.16.23292729. doi: 10.1101/2023.07.16.23292729.

BACKGROUND

While previous studies have reported associations of pericardial adipose tissue (PAT) with cardiovascular diseases such as atrial fibrillation and coronary artery disease, they have been limited in sample size or drawn from selected populations. Additionally, the genetic determinants of PAT remain largely unknown. We aimed to evaluate the association of PAT with prevalent and incident cardiovascular disease and to elucidate the genetic basis of PAT in a large population cohort.

METHODS

A deep learning model was trained to quantify PAT area from four-chamber magnetic resonance images in the UK Biobank using semantic segmentation. Cross-sectional and prospective cardiovascular disease associations were evaluated, controlling for sex and age. A genome-wide association study was performed, and a polygenic score (PGS) for PAT was examined in 453,733 independent FinnGen study participants.

RESULTS

A total of 44,725 UK Biobank participants (51.7% female, mean [SD] age 64.1 [7.7] years) were included. PAT was positively associated with male sex (β = +0.76 SD in PAT), age ( = 0.15), body mass index (BMI; = 0.47) and waist-to-hip ratio ( = 0.55) (P < 1×10). PAT was more elevated in prevalent heart failure (β = +0.46 SD units) and type 2 diabetes (β = +0.56) than in coronary artery disease (β = +0.22) or AF (β = +0.18). PAT was associated with incident heart failure (HR = 1.29 per +1 SD in PAT [95% CI 1.17-1.43]) and type 2 diabetes (HR = 1.63 [1.51-1.76]) during a mean 3.2 (±1.5) years of follow-up; the associations remained significant when controlling for BMI. We identified 5 novel genetic loci for PAT and implicated transcriptional regulators of adipocyte morphology and brown adipogenesis (, and ) and regulators of visceral adiposity ( and ). The PAT PGS was associated with T2D, heart failure, coronary artery disease and atrial fibrillation in FinnGen (ORs 1.03-1.06 per +1 SD in PGS, P < 2×10).

CONCLUSIONS

PAT shares genetic determinants with abdominal adiposity and is an independent predictor of incident type 2 diabetes and heart failure.

背景

虽然先前的研究报告了心包脂肪组织（PAT）与心血管疾病如心房颤动和冠状动脉疾病之间的关联，但这些研究在样本量上存在局限性或来自特定人群。此外，PAT的遗传决定因素在很大程度上仍然未知。我们旨在评估PAT与现患和新发心血管疾病的关联，并阐明其在大型人群队列中的遗传基础。

方法

在英国生物银行中，使用语义分割技术训练一个深度学习模型，以从四腔磁共振图像中量化PAT面积。评估了横断面和前瞻性心血管疾病的关联，并对性别和年龄进行了控制。进行了全基因组关联研究，并在453,733名独立的芬兰基因研究参与者中检查了PAT的多基因评分（PGS）。

结果

共纳入44,725名英国生物银行参与者（女性占51.7%，平均[标准差]年龄64.1[7.7]岁）。PAT与男性（PAT中β = +0.76标准差）、年龄（ = 0.15）、体重指数（BMI； = 0.47）和腰臀比（ = 0.55）呈正相关（P < 1×10）。与冠状动脉疾病（β = +0.22）或房颤（β = +0.18）相比，现患心力衰竭（β = +0.46标准差单位）和2型糖尿病（β = +0.56）患者的PAT升高更为明显。在平均3.2（±1.5）年的随访期间，PAT与新发心力衰竭（PAT每增加1标准差，HR = 1.29[95%CI 1.17 - 1.43]）和2型糖尿病（HR = 1.63[1.51 - 1.76]）相关；在控制BMI后，这些关联仍然显著。我们确定了5个新的PAT遗传位点，并发现了脂肪细胞形态和棕色脂肪生成的转录调节因子（、和）以及内脏脂肪的调节因子（和）。PAT的PGS与芬兰基因研究中的2型糖尿病、心力衰竭、冠状动脉疾病和心房颤动相关（PGS每增加1标准差，OR为1.03 - 1.06，P < 2×10）。